Adult mammalian central nervous system (CNS) axons are unable to regenerate after injury, but immature CNS neurons regenerate axons robustly. In addition to the development of an inhibitory CNS environment, a developmental loss in neurons' intrinsic capacity for axon growth is thought to contribute to regeneration failure. For example, after birth, axonal outgrowth from rat retinal ganglion cells (RGCs, a type of CNS neuron) slows substantially. Similar developmental declines in axon growth ability have been observed in mammalian tissue explants of brainstem, cerebellum, entorhinal cortex, and retina. Various cell-autonomous factors such as cAMP and CREB, Bcl-2, Rho/ROCK, Cdh1-APC, and PTEN have been suggested to play roles in this process. However, manipulating these regulators of axon growth, even when simultaneously overcoming environmental inhibition, only partially restores regeneration, suggesting that additional intrinsic axon growth regulators remain to be identified.
The inability of axons to regenerate in the central nervous system (CNS) is a major barrier to recovery from a wide range of injuries and diseases, including traumatic brain injury (e.g., traumatic optic neuropathy), stroke (including ischemic optic neuropathy), spinal cord injury, multiple sclerosis, macular degeneration, glaucoma, and other neurodegenerative diseases (e.g. Parkinson's Disease). A treatment that can stimulate CNS axon regeneration would improve outcomes for all of these afflictions, and other conditions that disrupt CNS axon tracts.
Current approaches for stimulating CNS axon regeneration in injured adult neurons generally focus on methods to improve the environment of the injured CNS. Such methods include the modulation of inflammatory responses in the spinal cord, transplantation of stem cells, and neutralizing inhibitory signaling in the CNS environment. It would be desirable to develop a new class of methods, which can boost neurons' intrinsic propensity for axon growth.